Certain transition metals like nickel, chromium, and cadmium, are carcinogenic to humans, especially in the industrial environment (e.g., metallurgy and welding); however, the mechanisms of their carcinogenic activity remain obscure. In recent years, we have formulated a novel hypothesis that one such mechanism would involve metal-mediated oxidative damage to DNA and nuclear proteins. By testing that hypothesis, we revealed previously that the metals did, indeed, induce DNA base damage in vitro and in vivo in a way typical for oxygen radical attack. In 1995/96 we continued mechanistic studies on that hypothesis. Our in vitro study, focused on redox activity of nickel complex system with a metal-binding peptide, CH3CO-Cys-Ala-Ile-His-NH2 (L) (metal-binding motif of histone H3), confirmed its high catalytic potential toward oxidation of 2'-deoxy-guanosine (dG) to promutagenic 8-oxo-dG. That activity was assigned specifically to a weak Ni(II) complex with L-dimer, a minor constituent of the complex system. Another in vitro investigation, focused on 8-oxo-dGTPases, a class of enzymes which prevent incorporation of promutagenic 8-oxo-dGTP into genomic DNA, revealed inhibition by Ni(II) of such bacterial and human enzymes (MutT and MTH-1, respectively), a phenomenon that may augment oxidative DNA damage. In an in vivo experiment on the repair of oxidative DNA base damage, the damage was determined in kidneys and livers of F344 rats following a single i.p. injection of Ni(II) acetate. Damaged DNA bases were found in chromatin of both organs one day after treatment. However, in the liver, the damage was repaired promptly, whereas in the kidney it persisted for up to 2 weeks, implying inefficient DNA repair specifically in the kidney, the target organ for nickel carcinogenesis. The results may indicate Ni(II) mediation of oxidative DNA damage through direct (redox catalysis) and indirect (inhibition of DNA repair) mechanisms. Overall, our work yields data supporting the oxidative hypothesis of metal-mediated carcinogenesis and also provides an experimental basis for collaborative studies on oxidative damage by other carcinogenic insults (see ZO1 BC 05352 and ZO1 BC 05301).